The Role of Trop2 Cleavage Products in Prostate Tumorigenesis
Final rept. 1 Jul 2012-30 Jun 2014
CALIFORNIA UNIV LOS ANGELES
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We have now shown that Trop2 is a new regulator of stemprogenitor activity and tumorigenesis in the prostate. Trop2 is necessary for prostate cancer initiation. Trop2 controls self-renewal, proliferation and tissue hyperplasia through two cleavage products ICD and ECD generated by RIP. The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. Nuclear ICD is found in human prostate cancer but not in the cancer-adjacent benign tissue, suggesting a role for Trop2 cleavage in tumorigenesis. Heightened expression of Trop2 intracellular or extracellular domains are sufficient to initiate precursor lesions to prostate cancer in vivo. Importantly, we demonstrate that Trop2 loss of function cleavage mutants are deficient in inducing self-renewal and tumorigenesis in the prostate. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem- like properties of self-renewal and proliferation. Identifying the factors that regulate self-renewal and cancer initiation will enhance our understanding of the tumorigenic process and lead to the design of novel cancer therapies.
- Anatomy and Physiology
- Medicine and Medical Research